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1 if their two loci are very tightly linked. If the two loci are not linked, then the probability of observing complete cosegregation in all ten meioses will equal (/)1°, since the probability that any two randomly selected genes at loci which are not linked will cosegregate equals %. Thus, if complete cosegregation is observed, the relative probability that the two loci are tightly linked as opposed to not linked equals 1: (Yz)10 or 1024 to 1. The log of this ratio to the6 base 10 is known as the "log of the odds" or lod score which in this instance will be 3-01. In practice, the use of lod scores is more complex than this simple outline would suggest since three-generation families that are necessary for establishing linkage phase are often not available.7 In general, a positive lod score of 3 or greater is taken as proof of linkage, since, with a prior probability of about 1 in 50 for linkage between any two randomly selected loci, conditional odds of 1000 to 1 yield an overall probability of 1 in 20 that the observed cosegregation has occurred by chance. A negative lod score of - 2 is taken as strong evidence against linkage, this lesser degree of stringency reflecting the high prior probability of about 49 to 1 -

against linkage. Lod scores were originally conceived as a means of quantifying the probability of linkage in the study of mendelian disorders. For conditions that do not show clear single-gene inheritance it is much more difficult to establish rigid lod score criteria for proving or rejecting linkage. If a single locus plays an important part in the genesis of a disorder such as bipolar depression, then, with a little luck, the use of candidate loci or multiple loci selected from throughout the genome ("shotgun" genetics) might be helpful, although determining the lod score which provides proof of linkage may be difficult. However, if the polygenic contribution to the aetiology of bipolar depression consists of many non-allelic deleterious genes each of which contributes a small additive effect, it is very unlikely that linkage analysis will be helpful, especially if a proband has affected relatives on both sides of the family. To complicate matters further, other difficulties arise when the linkage approach is used for the study of complex disorders such as depression and schizophrenia. Some family members with an adverse genotype may be sign and symptom free-so-called reduced penetrance. In others, the underlying psychiatric diathesis may manifest in different ways (phenotypic heterogeneity), so it is not clear how they should be scored in a linkage study. Moreover, the likelihood of aetiological heterogeneity should always be borne in mind. It is obviously disappointing that the initial report of linkage between schizophrenia and loci on chromosome 5q8 has not been substantiated by studies in other families.9-11 It is equally disappointing that reanalysis12 of the linkage relation between loci on

chromosome llp and bipolar affective disorder in a large Amish kindred has failed to confirm the initial positive finding.13 Guidelines have been proposed for maximising the prospects of success and for ensuring the validity of results obtained.14 Suggestions include the use of new and better statistical techniques to assist in unravelling minor locus effects; stricter phenotype definition; the use of pedigrees with no bilineal transmission; and restriction of the analysis to affected individuals, which would obviate the problem of non-penetrance. Adherence to these guidelines should at least ensure that consistent diagnostic and interpretative criteria are adopted in future research efforts and thereby result in fewer disappointments and more rapid progress towards elucidation of basic molecular defects. 1. Robertson M. False start on manic depression. Nature 1989; 342: 222. 2. Gurling H. Genetic linkage and psychiatric disease. Nature 1990; 344: 298. 3. Edwards JH. Genetic linkage and psychiatric disease. Nature 1990; 344: 298-99. 4. Mandel JL. Dystrophin. The gene and its product. Nature 1989; 339: 584-86. 5. Kerem BS, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073-80. 6. Morton NE. Sequential tests for the detection of linkage. Am J Hum Genet 1955; 7: 277-318. 7. Yates JRW, Connor JM. Genetic linkage. Br J Hosp Med 1986; 36: 133-36. 8. Sherrington R, Brynjolfsson J, Petursson H, et al. Localisation of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336: 164-67. 9. Kennedy JL, Giuffra LA, Moises HW, et al. Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree. Nature 1988; 336: 167-70. 10. St Clair D, Blackwood D, Muir W, et al. No linkage of chromosome 5q11-q13 markers to schizophrenia in Scottish families. Nature 1989; 339: 305-09. 11. Detera-Wadleigh SD, Goldin LR, Sherrington R, et al. Exclusion of linkage to 5q11-q13 in families with schizophrenia and other psychiatric disorders. Nature 1989; 340: 391-93. 12. Kelsoe JR, Ginns EI, Egeland JA, et al. Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish. Nature 1989; 342: 238-42. 13. Egeland JA, Gerhard DS, Pauls DL, et al. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 1987; 325: 783-87. 14. Baron M. Genetic linkage in mental illness. Nature 1990; 346: 618.

GASTROENTEROLOGISTS IN SYDNEY— HISTOLOGY AND HELICOBACTER Each of the 6000 delegates attending the 4th World Congresses of Gastroenterology in Sydney, August 26-31, received a document containing no fewer than eight working party reports. Those on a new classification of gastritis and Helicobacter pylori were especially noteworthy. The new classification of gastritis is known as the Sydney system. In addition to the international panel of the working party, the European Pathologists Advisory Group has approved the final system. Gastritis is a histological diagnosis: 40% of patients with a normal endoscopic gastric mucosa have histological gastritis. However, endoscopic appearances can be recorded systematically, and it may eventually be possible to correlate such appearances with the histological picture. Consequently, classification of endoscopic gastritis was included. The Sydney system recognises only three main forms of gastritis-acute, in which the dominant cell is the

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neutrophil granulocyte; chronic, with dominant chronic inflammatory cells; and "special forms". Inflammation throughout the stomach-pangastritis--can be further characterised as antrum predominant or corpus predominant, or inflammation may be confined to one of these areas. Morphologically, five features should be graded none, mild, moderate, or severe-inflammation (usually the chronic inflammatory cells); atrophy (loss of gastric glands); activity (in chronic gastritis the quantity of neutrophil granulocytes); intestinal metaplasia (individual patterns may be recognised but not graded); and spiral bacteria (usually H pylori but very occasionally "Gastrospirillum hominis"). Other histological features such as cell mucin content, epithelial degeneration, foveolar hyperplasia, and oedema should be documented but not graded. The histological report, when possible, should also state a probable aetiology. Examples might include (a) H pylori-associated chronic gastritis of the antrum; (b) autoimmune-associated chronic pangastritis, corpus predominant with severe atrophy; or (c) drug-associated acute gastritis of the antrum. A few will still be idiopathic. Gastric atrophy, which usually follows H pylori gastritis, nearly always precedes gastric cancer. The histopathologist should be told of drug therapy, including any antimicrobial therapy within the previous four weeks. Such treatment could suppress H pylori, with temporary reversal to a more normal picture but later relapse, and lead to a false conclusion that gastritis is absent. Ideally endoscopy should not be carried out if the patient has received antimicrobial drugs, including bismuth, within the previous four weeks. The Sydney system can be used by general and specialist histopathologists, and is flexible enough to accommodate new discoveries. During presentation of the working party report "Helicobacter pylori: causal agent in peptic ulcer disease?" Dr D. Y. Graham (Houston, Texas) revealed the geographic and social patterns of H pylori, which indicate transmission by the faecal-oral route, and the importance of drinkingwater in some communities. High-income families have very low rates of H pylori whereas the lowest income families have very high rates. Other topics were the microbiology of stomach spiral bacteria, and methods for the detection of H pylori infection (Prof A. Lee, Sydney), and probable pathogenic mechanisms of H pylori infection in the stomach (Dr B. J. Marshall, Charlottesville, Virginia). Dr M. F. Dixon (Leeds) discussed the relation between chronic H pylori gastritis and peptic ulceration. For duodenal ulcer (DU) he delineated the importance of gastric metaplasia in the duodenum, which becomes infected with antral H pylori leading to duodenitis; acid and pepsin act on this damaged tissue to produce the ulcer. Finally, Dr A. T. R. Axon (Leeds) reviewed the eradication of H pylori in relation to DU relapse. Patients whose ulcers have healed, but in whom H pylori has not been eradicated, have an 84 % relapse rate of their DU vs 11 % if the bacterium has been eradicated. For anti-helicobacter therapy, a combination of three antimicrobial agents has given the highest eradication rates, but is associated with some side-effects. (Diarrhoea can be reduced by a low-fibre diet.) The formulation, and therefore therapeutic success, of drugs such as bismuth varies, and this must be borne in mind. The dosage schedule, relation to food, and length of treatment are important. The working party recommended a two-week course of a bismuth compound (either colloidal bismuth subcitrate or bismuth subsalicylate) one tablet four times a day before food, with metronidazole 400 mg thrice

daily and tetracycline hydrochloride 500 mg four times daily. Amoxycillin 500 mg four times a day may be substituted for tetracycline, but more patients are intolerant of amoxycillin. In developing countries up to 80% of H pylori strains are resistant to metronidazole; no studies have been reported of other triple therapy combinations. DU thought to result from non-steroidal antiinflammatory drugs or an underlying condition such as Crohn’s disease should not be treated with anti-helicobacter therapy. Mild DU could be treated initially with an H2-receptor antagonist, but patients with relapsing and complicated ulcers should be treated with triple therapy, in an attempt to eradicate H pylori. (Some workers recommend that before triple therapy ulcer healing should be ensured, for example with four weeks’ treatment with an H2-receptor antagonist. Also, the effectiveness of bismuth tablets may be increased if the tablet is dispersed in water for at least thirty minutes.) The working-party chairman, Prof G. N. J. Tytgat (Amsterdam), emphasised that DU is a multifactorial disease, with the interplay of acid attack and mucosal defence modulated by genetics, gender, smoking, age, and acid output, but he noted that "H pylori is undoubtedly the major factor". Will all gastroenterologists, and drug companies, come to agree with the conclusion of these working parties about the importance of H pylori in gastritis, peptic ulcer, and even gastric cancer?

TAINTED TREACLE It would be a palpable injustice to the Secretary of State for Health to assume that some parts of the health service in the UK were being neglected in the frenetic rush to introduce the "reforms "-or so he would have us believe. In the world

of the entrepreneurial manager acting in an open market, the uninitiated might suppose that postgraduate education of doctors would enjoy a low priority in the drive to meet commercial objectives. Not so. Even postgraduate education find its place in Mr Clarke’s vision of the bright future that awaits us. He lately assured those attending the Joint Meeting on Postgraduate Medical Education in York that "nothing could be further from the truth than the concerns of some people".1 In his speech he paid fulsome tributes to his own Standing Committee on Postgraduate Medical Education (SCOPME). Under their "able chairman", working to an "impressive agenda", they have carried out "sterling work" on medical audit, exchequer funding, and the necessary infrastructure for postgraduate medical education. Abandoning his customary pugnacious approach to the medical profession for a performance of unabashed unctuousness, he wants us to believe that all is clearly for the best in the sweetest if not the best of all possible worlds. But is this the case? Observers who have a memory for such things may recall the first report of SCOPME, issued only a few months after that august body was established by Mr darker Members of the committee expressed disquiet about much of the content of the White Paper and opined that the way in which it had been launched threatened postgraduate education. The timescale for consultation and implementation were too short and the proposals had not been tested. The Minister’s response is not known, save for one rather curious development which may be relevant. The Chief Medical Officer was asked to set up a second expert advisory group to advise on the structure of postgraduate medical education under the new dispensation. This group has also now